Abstract: Alzheimer's disease and related dementias (ADRD) are age-related neurodegenerative disorders that are rapidly increasing as US population age and disproportionately affecting ethnic/racial minorities. Latinos are the largest and fastest growing ethnic/racial minority in the United States and will account for 20% of the US senior population by year 2050. Additionally, average life expectancy at birth for Latinos (81.8y) exceeds that of Whites (78.8y) by 3-years in spite of SES disadvantages and disparately high levels of chronic disorders morbidity (e.g., diabetes).4-8 A growing US Latino senior population with excess risk for ADRD, including longer life expectancy is a significant problem for US public health. Lastly, there are critical gaps in scientific knowledge about ADRD and aging among diverse Latinos. In particular, the molecular determinants of neurocognitive aging and Latino longevity are largely unknown. DNA methylation (DNAm), which regulates gene expression, represents one of the biological processes by which the interplay of genes and environmental/lifestyle exposures may have profound and sustained effects on aging, cognitive decline and ADRD. The proposed project will leverage the unique data and resources of the Hispanic Community Health Study/Study of Latinos (SOL; baseline n=16,415) and Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA baseline n=9,652). SOL provides rich sociocultural, cardiometabolic risk factors and genetic information, while SOL-INCA provides neurocognitive aging and MCI phenotypes measured at two visits. Specifically, we will (1) investigate blood DNAm signatures of biological aging and their relationship to cognitive decline and MCI at midlife; (2) identify blood DNAm signatures of neurocognitive decline and MCI and examine whether they differ in the context of the APOE genotype, ancestry, and acculturation; (3) leverage available biomarkers and genome-wide genetic data and use multi-omic integrative approaches and Mendelian randomization analyses to identify functional gene networks and biological exposures that influence blood DNAm signatures of neurocognitive aging and MCI. The project will efficiently fill gaps in scientific knowledge about Latino longevity and neurocognitive aging and disorders.